The present invention relates generally to methods and devices for drug delivery and analyte extraction, and specifically to methods and devices for puncturing the outer layer of living skin and to methods and devices for transdermal drug delivery and analyte extraction.
A number of different methods have been developed to perform transdermal drug delivery and/or analyte extraction, including passive diffusion of a drug or analyte between a skin patch and skin, as well as active processes such as iontophoresis, sonophoresis, electroporation, and chemically enhanced diffusion. These methods are primarily used for generating transdermal movement of small molecules, but generally do not enhance the motion of large molecules through the 10-50 micron thick outermost layer of the skin, the stratum corneum epidermidis.
In an article, xe2x80x9cMicromachined needles for the transdermal delivery of drugs,xe2x80x9d IEEE 11th Annual International Workshop on Micro-Electro-Mechanical Systems (1998), pp. 494-498, which is incorporated herein by reference, Henry et al. discuss a method of mechanically puncturing the skin with microneedles in order to increase the permeability of skin to a test drug. In the article, microfabrication techniques are described to etch an array of needles in silicon, and experiments performed on cadaver skin with the needle array demonstrated an increase in permeability subsequent to puncture of the skin. The needles are created with a predetermined length, and penetrate to the same depth from the skin surface, regardless of the local thickness of the stratum corneum. It is known that if the needles are longer than the local thickness, then the underlying epidermal tissue may be injured, while if the needles are too short, channel formation through the stratum corneum may be incomplete.
U.S. Pat. No. 4,775,361 to Jacques et al., U.S. Pat. No. 5,165,418 to Tankovich, and U.S. Pat. No. 5,423,803 to Tankovich et al., and PCT Publication WO 97/07734 to Eppstein et al., which are incorporated herein by reference, describe methods of using laser pulses to locally heat the stratum corneum to about 120xc2x0 C., thereby causing local ablation, in order to cause a single hole to develop in the stratum corneum through which large molecules may pass. Whereas some selectivity of ablation depth can be attained by varying the wavelength of the laser pulse, no feedback mechanism is disclosed whereby the laser pulses are terminated upon generation of the necessary damage to the stratum corneum.
PCT Publication WO 97/07734 also discloses thermal ablation of the stratum corneum using an electrically resistive element in contact with the stratum corneum, such that a high current through the element causes a general heating of tissue in its vicinity, most particularly the stratum corneum. As above, no means are disclosed to terminate current flow upon sufficient disruption of the stratum corneum. Additionally, thermal characteristics of skin vary highly across different areas of an individual""s skin, as well as among a group of subjects, making optimal thermal dosages, which produce the desired ablation without causing pain, very difficult to determine.
Electroporation is also well known in the art as a method to increase pore size by application of an electric field. This process is described in an article by Chizmadzhev et al., entitled xe2x80x9cElectrical properties of skin at moderate voltages,xe2x80x9d Biophysics Journal, February, 1998 , 74(2), pp. 843-856, which is incorporated herein by reference. Electroporation is disclosed as a means for transiently decreasing the electrical resistance of the stratum corneum and increasing the transdermal flux of small molecules by applying an electric field to increase the size of existing pores. Electroporation generally does not produce pores of sufficient diameter to pass large molecules therethrough. Additionally, optimal voltage profiles are difficult to determine because of naturally occurring variations as described hereinabove, as well as the lack of an accurate feedback mechanism to indicate achievement of the desired pore enlargement. If excessive voltage is applied, an irreversible breakdown occurs, resulting in damage to the skin and possible sensations of pain.
U.S. Pat. No. 5,019,034 to Weaver et al., which is incorporated herein by reference, describes apparatus for applying high voltage, short duration electrical pulses on the skin to produce electroporation, and states that xe2x80x9c . . . reversible electrical breakdown . . . along with an enhanced tissue permeability, is the characteristic effect of electroporation.xe2x80x9d
U.S. Pat. Nos. 5,885,211, 6,022,316, 6,142,939 and 6,173,202 to Eppstein et al., which are incorporated herein by reference, describe methods for forming micropores in the stratum corneum by heating tissue-bound water above the vapor point with a heat conducting element, so as to enhance transdermal transport of an analyte or active substance. Further enhancement techniques include the use of sonic energy, pressure, and chemical enhancers.
U.S. Pat. No. 3,964,482 to Gerstel, U.S. Pat. No. 6,050,988 to Zuck, and U.S. Pat. No. 6,083,196 to Trautman et al., which are incorporated herein by reference, describe other apparatus and methods for facilitating transdermal movement of a substance.
U.S. Pat. No. 6,148,232 to Avrahami, which is incorporated herein by reference, describes apparatus for applying electrodes at respective points on skin of a subject and applying electrical energy between two or more of the electrodes to cause resistive heating and subsequent ablation of the stratum corneum primarily in an area intermediate the respective points. Various techniques for limiting ablation to the stratum corneum are described, including spacing of the electrodes and monitoring the electrical resistance of skin between adjacent electrodes.
Electrosurgery is commonly used during surgical procedures today, particularly in endoscopic and laparoscopic surgery where direct access to the tissue being dissected is limited. Electrosurgery involves applying radio frequency electric current to electrodes which are used to sever tissue or achieve homeostasis. A publication entitled xe2x80x9cInstruction Manual for the Force 2 Electrosurgical Generatorxe2x80x9d (Valleylab/Tyco Healthcare Group LP, Boulder, Colo.), which is incorporated herein by reference, describes the modes of operation of electrosurgical devices.
Three surgical effects can be achieved with electrosurgery. At relatively low power settings, current passing through tissue causes heating of the tissue due to the high frequency and the electrical resistance thereof. As the tissue is heated, water within the tissue is driven out, leading to desiccation of the tissue. At higher power levels, the water in the tissue may vaporize before it leaves the cells, causing the cells to explode. Moving the electrode into contact with new tissue causes new cells to explode, and results in electrosurgical cutting. Alternatively, small sparks may jump across gaps, causing cells to explode or ablate. Due to the extreme concentration of current, the cutting is particularly efficient with short sparks.
Applying electrical power intermittently, having higher peak voltages but the same average power as is used in electrosurgical cutting, allows for desiccation of the tissue near the electrode without bursting the cells. As water leaves the cells, the resistance of the cells increases until the resistance of the tissue is greater than that of the medium surrounding the tissue and electrode. If the peak voltage is high enough, a long spark may occur between the electrode and surrounding tissue (where minimal desiccation has occurred). The spark causes charring and cauterization of the tissue, the degree of which is determined by the length of time sparks have impinged the tissue.
U.S. Pat. No. 6,159,194 to Eggers et al., which is incorporated herein by reference, describes electrosurgical apparatus and methods for inducing tissue contraction, without ablation or dissociation of surrounding tissue, in order to reduce wrinkles in skin.
U.S. Pat. No. 6,090,106 to Goble et al., which is incorporated herein by reference, describes monopolar and bipolar electrosurgical instruments for ablating gross tissue, such as the prostate or endometrial tissue.
U.S. Pat. Nos. 6,066,134 and 6,024,733 to Eggers et al., which are incorporated herein by reference, describe electrosurgical apparatus and methods for ablating outer layers of skin for the treatment of unwanted tissue pigmentations, melanomas, and other skin disorders.
U.S. Pat. No. 4,943,290 to Rexroth et al., which is incorporated herein by reference, describes electrosurgical apparatus in which a nonconductive fluid is transported to the region of the electrode to isolate the electrode and prevent undesirable damage of surrounding tissue.
It is an object of some aspects of the present invention to provide improved apparatus and methods for transdermal delivery of an active substance.
It is a further object of some aspects of the present invention to provide improved apparatus and methods for transdermal analyte extraction.
It is yet a further object of some aspects of the present invention to provide improved apparatus and methods for creating narrow channels through the stratum corneum of living skin by puncturing.
It is still a further object of some aspects of the present invention to provide improved apparatus and methods for reducing sensation and minimizing damage to skin underlying the stratum corneum during channel creation.
It is an additional object of some aspects of the present invention to provide improved apparatus and methods for controlling the timing of channel creation.
It is another object of some aspects of the present invention to provide improved apparatus and methods for puncturing the skin and/or transdermally delivering an active substance and/or transdermally extracting an analyte, using a miniature, self-contained device.
It is yet another object of some aspects of the present invention to provide improved apparatus and methods for transdermally delivering an active substance using a standard medical skin patch.
In preferred embodiments of the present invention, a device for enhancing transdermal movement of a substance comprises: (a) a housing, for supporting at least one spark-generating electrode in a vicinity of the skin of a subject; and (b) a control unit, coupled to the housing, which causes electrical current to pass through the electrode and generate one or more sparks between the electrode and the stratum corneum epidermidis, in order to create at least one micro-channel in the stratum corneum to enable or augment transdermal movement of the substance. Preferably, the control unit comprises circuitry to control the magnitude, frequency, and/or duration of the electrical energy delivered to the electrode, so as to control spark generation, and thus micro-channel formation.
Alternatively or additionally, current may be applied to the skin in order to ablate the stratum corneum, substantially without causing sparks until the ablation has reached a certain depth. In this case, spark generation may be used as a form of feedback, which indicates that the desired depth has been reached and current application should be terminated. For these applications, the electrodes are preferably shaped and/or supported in a housing which is conducive to facilitating ablation of the stratum corneum to the desired depth, but not beyond that depth. If appropriate, the control unit may determine whether a number of sparks or a rate of spark generation exceeds a threshold number or rate, and terminate or reduce current application responsive thereto.
The term xe2x80x9cmicro-channelxe2x80x9d as used in the context of the present patent application refers to a pathway generally extending from the surface of the skin through all or a significant part of the stratum corneum, through which pathway molecules can diffuse. Preferably, micro channels allow the diffusion therethrough of large molecules at a greater rate than the same molecules would diffuse through pores generated by electroporation.
It is believed that such micro-channels are formed, in accordance with a preferred embodiment of the present invention, due to spark generation between the electrode and the skin as a result of sufficiently large applied voltages. Unlike many methods of electrically-promoted drug delivery known in the art, such as iontophoresis and electroporation, this embodiment of the present invention enables relatively large channels to be formed, through which even large molecules of the active substance can pass rapidly, without the necessity of ionizing or polarizing the molecules. Moreover, unlike the device described in the above-cited U.S. Pat. No. 6,148,232 to Avrahami, which does describe the creation of micro-channels in the stratum corneum, this particular embodiment preferably creates the channels in the stratum corneum by generating sparks which generally explosively remove the stratum corneum in a very localized area, in a manner analogous to that used in electrosurgery. Nevertheless, it is to be understood that, for certain applications, some of the apparatus and techniques described in the Avrahami patent may be adapted for use with preferred embodiments of the present invention, mutatis mutandis. In particular, as described herein, electric current may be applied to the skin in order to ablate the stratum corneum, without necessarily generating sparks, using some of the same parameters (e.g., frequency or amplitude) as those described in the Avrahami patent.
In general, the stratum corneum epidermidis (the superficial layer of the epidermis) demonstrates a significantly higher resistance to the passage of molecules therethrough than does the underlying epidermal tissue. It is therefore an object of these preferred embodiments of the present invention to form micro-channels in the stratum corneum by ablating the stratum corneum, in order to increase conductance of the substance therethrough, and to generally not directly affect or damage epidermal tissue underlying the stratum corneum or in the innervated dermis. Limiting ablation substantially to the non-innervated stratum corneum is expected to decrease or eliminate the subject""s sensations, discomfort, or pain responsive to use of these embodiments of the present invention, particularly as compared with other procedures known in the art. It is noted, however, that for some applications it may be desirable to ablate tissue to a depth beyond the stratum corneum.
In some preferred embodiments of the present invention, the housing supports an array of electrodes, preferably closely-spaced electrodes, which act together to produce a high micro-channel density in an area of the skin under the housing. Preferably, the control unit and/or associated circuitry sequentially or simultaneously evaluates the current flow through each electrode, or a subset of the electrodes, in order to determine, for example: (a) when one spark or a desired number of sparks have formed responsive to the applied field, or (b) when a property (such as electrical impedance) of the skin has changed, thereby indicating successful ablation of the stratum corneum. Responsive thereto, the control unit discontinues application of the field. In a preferred embodiment, since the formation of a spark between an electrode and the skin typically leads to ablation of at least some stratum corneum, the degree of ablation is preferably controlled by allowing a predetermined number of sparks to occur. Alternatively, the total current flow to the skin is used as a control parameter. Additionally or alternatively, a strictly time-based control is used to control the degree of ablation (e.g., a predetermined voltage applied for a predetermined time).
In further preferred embodiments of the present invention, a concentric electrode pair is formed by employing the housing as a return path for the current passing from the electrode to the skin. It is to be understood that use of a conductive portion of the housing as a return path is one preferred method for achieving the goals of these embodiments of the present invention. For other applications, however electrodes coupled to the housing may be used, as well. Preferably, the housing has a relatively large contact surface area with the skin, resulting in relatively low current densities in the skin near the housing, and thus no significant heating or substantial damage to the skin at the contact surface. In proximity to the inner electrode, by contrast, the high-energy applied field typically induces very rapid heating and ablation of the stratum corneum. It will be appreciated that a plurality of inner electrodes may be provided, adjacent to or surrounded at least in part by one or more other electrodes which define the return path.
Typically, the housing is adapted to contain a pharmaceutical substance, e.g.: (a) an active substance, such as insulin or dimenhydrinate, (b) a vaccine, (c) a substance to aid in diagnosis of a condition, or (d) substantially any other pharmaceutical or other type of material suitable for transdermal administration. Following ablation at one or more sites on the skin, the substance is preferably actively or passively delivered to the ablated sites. For some applications, the active substance is in the form of a gel, which is applied to the housing near the electrodes at the time of manufacture of the device, or, as appropriate, shortly prior to the use of the device.
Alternatively, the device creates micro-channels, as described herein, and is then removed from the skin, in order to enhance the transdermal delivery of a substance into or out of a commercially-available skin patch subsequently placed on the skin.
For some applications, it is desirable to stop transdermal flow of a substance (e.g., an analyte or a drug) at a certain point after ablation of the stratum corneum. Preferably, the flow is stopped by application of a current, e.g., one having an AC and/or a DC component, which at least in part seals the pores induced in the stratum corneum. For example, the applied current may be configured so as to have a local coagulation effect, optionally using parameters known in the art of electrosurgery. Alternatively or additionally, the current may induce the coagulation of a material in the pore, such as a natural body fluid or an externally-applied material.
In some preferred embodiments of the present invention, a material is applied between the electrodes and the skin so as to aid in attaining good electrical contact between the electrodes and the skin. In particular, this embodiment is appropriate for applications in which the electrodes do not make physical contact with the skin, and instead generate sparks which ablate the stratum corneum. In a preferred application, the material comprises a liquid, gel, cream or disposable film or patch, and, if appropriate, a substance such as a drug intended for transdermal delivery.
For some applications, electrodes which substantially do not contain metal are employed to ablate the stratum corneum. Alternatively or additionally, drug films or coatings are applied to the surface of the electrodes, or are impregnated within the electrodes, and the electrodes themselves are porous or otherwise configured to allow designated materials to be delivered through the skin. Further alternatively or additionally, a charge-limiting substance for delivery into the body may be integrated into the electrode itself, so as to terminate current flow through the electrode when a sufficient quantity of the substance has been delivered.
It will be appreciated that a range of manufacturing techniques may adapted for the production of devices such as those described herein. For example, electrodes may be etched onto a printed circuit board (PCB), or they may be electroformed. If appropriate, the electrodes may be printed onto a surface, preferably incorporating a substance for transdermal delivery into the printed electrode. Alternatively or additionally, electrodes may be stamped or laser-cut out of thin sheet metal, and sandwiched between insulating spacers.
Similarly, it will be appreciated that the transdermal movement of a range of molecules may be facilitated using the techniques provided by preferred embodiments of the present invention, including both small molecules and molecules having molecular weights greater than, for example, 500 dalton. Similarly, hydrophilic molecules, which are normally rejected by the stratum corneum, are particularly well-suited for use with these embodiments. It is noted that prior art transdermal drug delivery techniques often required finding drugs that are neither hydrophilic nor hydrophobic, thus compromising to some extent the availability of many drugs for these applications.
As appropriate, methods and apparatus described in one or more of the following applications, which are assigned to the assignee of the present patent application and are incorporated herein by reference, may be adapted for use with techniques provided by some embodiments of the present invention:
A U.S. patent application entitled, xe2x80x9cHandheld apparatus and method for transdermal drug delivery and analyte extraction,xe2x80x9d filed Apr. 23, 2001.
That application describes a device for treating skin on the body of a subject, including:
a plurality of electrodes, which are adapted to be placed in contact with the skin and then moved across the skin while maintaining electrical contact with the skin; and
a power source, which is adapted to apply a current between two or more of the plurality of electrodes at the same time as the electrodes are being moved across the skin.
In a preferred embodiment, the device includes a marking unit, adapted to apply a substance to the skin so as to demarcate a region of the skin to which the current is applied. Alternatively or additionally, the device includes one or more protrusive elements, adapted to press the skin so as to demarcate a region of the skin to which the current is applied.
In a preferred embodiment, the substance application unit includes:
a spool, adapted to rotate as the device moves across the skin; and
a substance application strip having the substance applied thereto, which strip is adapted to be disposed around the spool, so as to unwind from the spool as the device is moved across the skin, and so as to cover the site on the skin to which the current is applied.
That application also describes a device for treating skin on the body of a subject, including:
a roller, adapted to rotate when it is moved across the skin;
a plurality of electrodes, disposed over a surface of the roller, so as to be placed in sequence into contact with the skin as the roller is moved across the skin; and
a power source, which is adapted to drive a current through each electrode when the electrode is in contact with the skin.
That application further describes a device for treating skin on the body of a subject, including:
a housing;
a plurality of electrodes, disposed on a surface of the housing, which are adapted to be placed in contact with the skin;
a motion sensor, which is adapted to generate a sensor signal responsive to motion of the housing; and
a control unit, which is adapted to receive the sensor signal, to determine, responsive thereto, a physical disposition of the device, and to control current flow to the plurality of electrodes responsive to determining the physical disposition.
That application still further describes a device for treating skin on the body of a subject, including:
a plurality of receiving electrodes, which are adapted to be placed in contact with the skin so as to provide electrical contact with the skin;
a driving electrode, which is adapted to be passed across the receiving electrodes so as to create electrical contact with a first one of the receiving electrodes prior to creating electrical contact with a second one of the receiving electrodes; and
a power source, which is adapted to drive the driving electrode to apply a first current to the first receiving electrode when the driving electrode is in electrical contact with the first receiving electrode, and to apply a second current to the second receiving electrode when the driving electrode is in electrical contact with the second receiving electrode.
A U.S. patent application entitled, xe2x80x9cElectronic card for transdermal drug delivery and analyte extraction,xe2x80x9d filed on even date with the present patent application.
That application describes a device for delivering a substance to skin of a subject, including:
a substance storage unit, which is adapted to store the substance;
an analysis unit, which is adapted to receive a portion of a body fluid of the subject, to analyze the portion, and to generate a signal responsive to the analysis of the portion;
one or more electrodes, which are adapted to be placed at respective sites on the skin; and
a substance delivery unit, which is adapted to receive the signal, and, responsive thereto, to drive at least some of the one or more electrodes to apply to respective ones of the sites on the skin a current capable of ablating stratum corneum epidermidis of the skin, so as to facilitate delivery of the substance from the storage to drive to apply unit through the skin at the respective ones of the sites.
In a preferred embodiment, the substance delivery unit is adapted:
to designate at a first time a first number of the one or more electrodes to drive to apply the current, responsive to a desired rate of delivery of the substance during a first time period, and
to designate at a second time a second number of the one or more electrodes to drive to apply the current, responsive to a desired rate of delivery of the substance during a second time period, the second number being different from the first number.
Alternatively or additionally, the device includes a sensor, adapted to measure a physiological parameter of the subject and to generate a sensor signal responsive thereto, wherein the substance delivery unit is adapted to designate the second time responsive to the sensor signal. The sensor may be adapted to measure a physiological parameter selected from the list consisting of: transepidermal water loss (TEWL), a property of the skin, temperature, blood pressure, heart rate, and respiration rate.
For some applications, at least one of the one or more electrodes is adapted to apply to the skin a substantially DC current capable of enhancing by means of iontophoresis the passage of a material through the skin.
Alternatively or additionally, the device includes a communications unit, which is adapted to receive the signal and, responsive thereto, to transmit information to a computer external to the device. Further alternatively or additionally, the device includes a communications unit, which is adapted to receive an instruction from a remote computer, and the substance delivery unit is adapted to modify, responsive to the instruction, a parameter of the current.
If appropriate, the analysis unit may be adapted to drive a subset of the one or more electrodes to apply a current to the skin, so as to facilitate extraction therefrom of an analyte in blood of the subject. Alternatively or additionally, the analysis unit may be adapted to analyze blood of the subject, urine of the subject, and/or saliva of the subject, and to generate the signal responsive thereto.
Israel Patent Application 136,008, entitled, xe2x80x9cElectrically-mediated transdermal drug injection,xe2x80x9d filed May 7, 2000.
There is therefore provided, in accordance with a preferred embodiment of the present invention, a device for ablating stratum corneum epidermidis of skin on the body of a subject, including:
a housing;
a substance storage unit, adapted to store a substance;
an electrode, coupled to the housing; and
a control unit, which is adapted to apply electrical energy to the electrode when the electrode is in a vicinity of the skin, and to configure the energy so as to be capable of generating one or more sparks between the electrode and the skin which are capable of causing ablation of an area of the stratum corneum, so as to facilitate passage of the substance from the storage unit through the ablated area of the skin.
There is further provided, in accordance with a preferred embodiment of the present invention, a device for facilitating passage of a substance through skin on the body of a subject, including:
an electrode;
a housing, adapted to be placed on the skin and to support the electrode in a position not in contact with the skin; and
a control unit, adapted to apply electrical energy to the electrode capable of ablating stratum corneum epidermidis of the skin, so as to facilitate transdermal passage of the substance.
In a preferred embodiment, the control unit is adapted to apply electrical energy capable of generating a spark between the electrode and the skin, so as to ablate the stratum corneum.
Alternatively or additionally, the device includes a conductive material, adapted for placement between the electrode and the skin so as to facilitate current flow between the electrode and the skin.
There is yet further provided, in accordance with a preferred embodiment of the present invention, a device for facilitating passage of a substance through skin on the body of a subject, including:
an electrode;
a housing, adapted to be placed on the skin and to support the electrode in a position in which the electrode is in contact with the skin and substantially does not extend past a plane defined by a surface of the skin; and
a control unit, adapted to drive the electrode to apply to the skin a current capable of ablating stratum corneum epidermidis of the skin, so as to facilitate transdermal passage of the substance.
There is still further provided, in accordance with a preferred embodiment of the present invention, a device for facilitating passage of a substance through skin on the body of a subject, including:
an electrode; and
a control unit, adapted to:
drive the electrode to apply to the skin a current capable of ablating stratum corneum epidermidis of the skin, so as to facilitate transdermal passage of the substance,
detect generation of at least one spark responsive to application of the current, and
modify a parameter of the current responsive to detecting the generation of the at least one spark.
In a preferred embodiment, the control unit is adapted to terminate application of the current responsive to detecting the generation of the at least one spark. Alternatively or additionally, the control unit is adapted to determine whether a number of sparks generated responsive to the applied current exceeds a threshold number. Further alternatively or additionally, the control unit is adapted to determine whether a rate of spark generation responsive to the applied current exceeds a threshold rate.
There is also provided, in accordance with a preferred embodiment of the present invention, a device for facilitating passage of a substance through skin on the body of a subject, including:
an electrode, a first portion of which having a first cross-section, and a second portion of which having a second cross-section which is different from the first cross-section, the electrode being adapted to be placed such that the first portion is in contact with the skin; and
a control unit, adapted to drive the electrode to apply an electric current to the skin capable of ablating stratum corneum epidermidis thereof, so as to facilitate passage through the skin of the substance.
Preferably, the control unit is adapted to detect a transition from (a) a first time, in which the second portion is substantially not in contact with the skin, to (b) a second time, in which the second portion is in contact with the skin. Typically, the second portion is electrically conductive. Alternatively, the second portion is substantially electrically non-conductive. Still further alternatively, the second portion includes a partially non-conductive material.
In a preferred embodiment, the second cross-section has a characteristic diameter larger than a characteristic diameter of the first cross-section.
The first portion is typically adapted for insertion into the skin responsive to ablation of the stratum corneum.
In a preferred embodiment, the control unit is adapted to modify a parameter of the current responsive to detecting the transition.
For some applications, the second portion includes the substance.
There is additionally provided, in accordance with a preferred embodiment of the present invention, a device for facilitating passage of a substance through skin on the body of a subject, including:
a longitudinal electrode, including:
a first portion, having a first property at a first longitudinal site of the electrode, and
a second portion, having a second property at a second longitudinal site of the electrode, the second property being different from the first property, the electrode being adapted to be placed such that the first portion is in contact with the skin; and
a control unit, adapted to drive the electrode to apply an electric current to the skin capable of ablating stratum corneum epidermidis thereof.
Preferably, the control unit is adapted to detect a transition from (a) a first time, in which the second portion is substantially not in contact with the skin, to (b) a second time, in which the second portion is in contact with the skin.
In a preferred embodiment, the second portion includes a measured quantity of the substance.
The first portion typically has an electrical property, and the second portion has an electrical property different from the electrical property of the first portion. Alternatively or additionally, the first portion has a material property, and wherein the second portion has a material property different from the material property of the first portion.
Preferably, the control unit is adapted to modify a parameter of the current responsive to detecting the transition.
There is yet additionally provided, in accordance with a preferred embodiment of the present invention, a device for facilitating delivery of a substance through skin on the body of a subject, including:
an electrode, including the substance; and
a control unit, adapted to drive the electrode to apply to the skin a current capable of ablating stratum corneum epidermidis of the skin, so as to facilitate delivery of the substance from the electrode through the skin.
There is still additionally provided, in accordance with a preferred embodiment of the present invention, a device for facilitating passage of a substance through skin on the body of a subject, including:
a housing;
an ablating electrode, fixed to the housing and adapted to apply a current to the skin capable of ablating stratum corneum epidermidis in a vicinity of the ablating electrode, so as to facilitate transdermal passage of the substance; and
a non-ablating electrode, fixed to the housing and adapted to provide a return path for the current, substantially without ablating stratum corneum in a vicinity of the non-ablating electrode.
Preferably, the ablating electrode includes at least 100 ablating electrodes. And the non-ablating electrode includes at least 3 non-ablating electrodes. Alternatively, the non-ablating electrode includes two non-ablating electrodes, and the device includes a control unit, adapted to measure electrical impedance between the two non-ablating electrodes.
There is also provided, in accordance with a preferred embodiment of the present invention, a device for facilitating passage of a substance through skin on the body of a subject, including:
an electrode, adapted to be applied to the skin;
a mechanical sensor, adapted to detect an indication of a contact force between the electrode and the skin and to generate a sensor signal responsive thereto; and
a control unit, adapted to receive the sensor signal and, responsive thereto, to drive the electrode to apply a current to the skin capable of ablating stratum corneum epidermidis thereof, so as to facilitate transdermal passage of the substance.
There is further provided, in accordance with a preferred embodiment of the present invention, a device for facilitating passage of a substance through skin on the body of a subject, including:
an electrode; and
a control unit, adapted to drive the electrode to apply current to the skin in a series of bursts, so as to ablate stratum corneum epidermidis of the skin and facilitate transdermal passage of the substance.
Preferably, the control unit is adapted to provide a time period between successive bursts sufficient to allow recovery, at least in part, of a skin property changed by the application of the current.
Preferably, the control unit is adapted to provide a time period between successive bursts sufficient to allow recovery, at least in part, of a level of electrical impedance of the skin that is changed by the application of the current.
In a preferred embodiment, the control unit is adapted to measure an electrical property of the skin during one or more of the bursts, and to modify a parameter of the current responsive to measuring the property. For example, the control unit may be adapted to compare a value of the property measured during one of the bursts with a value of the property measured during another one of the bursts, and to modify a parameter of the current responsive to comparing the values. Alternatively or additionally, the control unit may be adapted to detect, during a single burst, a change in a value of the property, and to modify the parameter of the current responsive to detecting the change.
Typically, the control unit is adapted to provide a period between two of the bursts which is greater than about 1 millisecond and less than about 50 milliseconds.
There is still further provided, in accordance with a preferred embodiment of the present invention, a device for facilitating passage of a substance through skin on the body of a subject, including:
a housing;
an electrode coupled to the housing, the electrode including:
a first portion, adapted for insertion into the skin, and
a second portion, adapted to remain outside the skin, and to convey a compressive force from the housing to the skin; and
a control unit, adapted to drive the electrode to apply a current to the skin capable of ablating stratum corneum epidermidis of the skin, so as to facilitate passage of the substance through the skin.
Preferably, a characteristic diameter of the second portion of the electrode is such as to inhibit insertion of the second portion into the skin.
For some applications, the second portion is substantially non-conductive.
Preferably, the control unit is adapted to detect contact of the second portion and the skin, and to terminate the current responsive thereto, so as to inhibit insertion of the second portion into the skin.
In a preferred embodiment, the control unit is adapted to detect one or more sparks generated responsive to the current.
The present invention will be more fully understood from the following detailed description of the preferred embodiments thereof, taken together with the drawings in which: